PIM (acyl glyceryl phosphatidylinositol manno-oligosaccharide) is an immunogenic component of mycobacterial cell walls which is capable of treating or preventing inflammatory or immune cell-mediated diseases and disorders such as asthma, allergic rhinitis, dermatitis, psoriasis, inflammatory bowel disease including Crohn's disease and ulcerative colitis, rheumatoid arthritis, multiple sclerosis, diabetes, systemic lupus erythematosis and atherosclerosis.
WO 02/02140 discloses an immunogenic composition comprising PIM which is effective in the treatment and prevention of Th2 mediated disease, particularly asthma. In particular, the PIM vaccine appears to act by suppressing the allergic response which would normally cause a recruitment and activation of eosinphils to the lung causing chronic swelling and inflammation of the airways that affects the breathing of sufferers. Experiments using a mouse model of airway eosinophilia illustrated that administration of the PIM composition resulted in a dose dependent decrease in the number of eosinophils in the lungs of such mice.
Currently a heterogeneous mixture of PIM species is produced by isolating the PIM fraction from dead mycobacterial organisms using a series of chemical purification steps as disclosed in WO 02/02140 and in Severn et al, 1997. This purification process is laborious and not suitable for large scale manufacture of PIM.
In particular, the PIM fraction can be contaminated by lipopolysaccharides such as endotoxins which are also known to induce an immunological response and therefore may mask or interfere with the biological activity of such a PIM extract.
PIM exists in nature in many different forms. For example the number of mannose and acyl residues may vary. Different acyl forms have been purified using sophisticated analytical tools such as MALDI-MS and two-dimensional NMR. (Gilleron et al 2001; Gilleron et al 2003). In particular native PIM2 and PIM6 have been purified, characterised and their biological activity demonstrated in that these compounds stimulate macrophages to produce cytokines.
In addition, a number of glycophospholipid compounds have been synthesised and either polymerised to form synthetic cell membranes, bilayers, films, liposomes for use in drug delivery systems (U.S. Pat. No. 6,071,532; U.S. Pat. No. 6,171,614; JP 06-271597) or used in therapeutic compositions for treating inflammatory disorders (US 2002/0028823; U.S. Pat. No. 6,024,940; US 2002/0032195; US 2003/0008848; US 2003/0022913).
It is an object of the present invention to provide novel synthetic molecules having biological activity, including PIM or PIM-like activity, which may be synthesised using highly efficient and economical chemical processes suitable for manufacture on a large scale and free of endotoxin and/or to provide the public with a useful choice.